The Proteomic Landscape of <em>CTNNB1</em> Mutated Low-Grade Early-Stage Endometrial Carcinomas

Endometrial carcinoma is the most frequent gynecologic malignancy in western countries. In recent years, mutations in CTNNB1 have been associated with worse prognosis in low-risk carcinomas. However, there is a lack of understanding of the proteomic implications of CTNNB1 mutations in these tumors. In this study, we performed shotgun proteomics using Formalin Fixed Paraffin Embedded (FFPE) tissue samples of CTNNB1 mutated and wild-type low-risk endometrial carcinomas. A publicly available proteomic and transcriptomic database was used to validate results. Differential protein expression and Gene Set Enrichment Analysis revealed dysregulation of pathways associated with cell keratinization, immune response modulation, and intracellular calcium regulation. CTNNB1 mutated tumors showed immune dysregulation at multiple levels including cytokine secretion, cell adhesion, and lymphocyte activation. These results were supported by tissue multiplex immunofluorescence analysis, demonstrating reduced CD8 tumor infiltrating lymphocytes and different immune spatial interaction patterns. Intracellular calcium dysfunction was associated with key transcript dysregulation. We found an increased expression of CAMK2A and ROR2, suggesting a potential role for non-canonical Wnt pathway activation in CTNNB1 mutated tumors.